Minimal/measurable residual disease in AML: a consensus document from the European
      LeukemiaNet MRD Working Party

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Abstract

Publisher's Note: There is a [Related article:] Blood Commentary on this article in this issue.

Abstract

Measurable residual disease (MRD; previously termed minimal residual disease) is an independent, postdiagnosis, prognostic indicator in acute myeloid leukemia (AML) that is important for risk stratification and treatment planning, in conjunction with other well-established clinical, cytogenetic, and molecular data assessed at diagnosis. MRD can be evaluated using a variety of multiparameter flow cytometry and molecular protocols, but, to date, these approaches have not been qualitatively or quantitatively standardized, making their use in clinical practice challenging. The objective of this work was to identify key clinical and scientific issues in the measurement and application of MRD in AML, to achieve consensus on these issues, and to provide guidelines for the current and future use of MRD in clinical practice. The work was accomplished over 2 years, during 4 meetings by a specially designated MRD Working Party of the European LeukemiaNet. The group included 24 faculty with expertise in AML hematopathology, molecular diagnostics, clinical trials, and clinical medicine, from 19 institutions in Europe and the United States.

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Detection of ultra-rare mutations by next-generation sequencing.

Michael W Schmitt, Scott Kennedy, Jesse Salk … (2012)

Next-generation DNA sequencing promises to revolutionize clinical medicine and basic research. However, while this technology has the capacity to generate hundreds of billions of nucleotides of DNA sequence in a single experiment, the error rate of ~1% results in hundreds of millions of sequencing mistakes. These scattered errors can be tolerated in some applications but become extremely problematic when "deep sequencing" genetically heterogeneous mixtures, such as tumors or mixed microbial populations. To overcome limitations in sequencing accuracy, we have developed a method termed Duplex Sequencing. This approach greatly reduces errors by independently tagging and sequencing each of the two strands of a DNA duplex. As the two strands are complementary, true mutations are found at the same position in both strands. In contrast, PCR or sequencing errors result in mutations in only one strand and can thus be discounted as technical error. We determine that Duplex Sequencing has a theoretical background error rate of less than one artifactual mutation per billion nucleotides sequenced. In addition, we establish that detection of mutations present in only one of the two strands of duplex DNA can be used to identify sites of DNA damage. We apply the method to directly assess the frequency and pattern of random mutations in mitochondrial DNA from human cells.

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Assessment of Minimal Residual Disease in Standard-Risk AML

Adam Ivey, Robert K. Hills, Michael A. Simpson … (2016)

Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission.

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EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes

J van Dongen, L Lhermitte, S Böttcher … (2012)

Most consensus leukemia & lymphoma antibody panels consist of lists of markers based on expert opinions, but they have not been validated. Here we present the validated EuroFlow 8-color antibody panels for immunophenotyping of hematological malignancies. The single-tube screening panels and multi-tube classification panels fit into the EuroFlow diagnostic algorithm with entries defined by clinical and laboratory parameters. The panels were constructed in 2–7 sequential design–evaluation–redesign rounds, using novel Infinicyt software tools for multivariate data analysis. Two groups of markers are combined in each 8-color tube: (i) backbone markers to identify distinct cell populations in a sample, and (ii) markers for characterization of specific cell populations. In multi-tube panels, the backbone markers were optimally placed at the same fluorochrome position in every tube, to provide identical multidimensional localization of the target cell population(s). The characterization markers were positioned according to the diagnostic utility of the combined markers. Each proposed antibody combination was tested against reference databases of normal and malignant cells from healthy subjects and WHO-based disease entities, respectively. The EuroFlow studies resulted in validated and flexible 8-color antibody panels for multidimensional identification and characterization of normal and aberrant cells, optimally suited for immunophenotypic screening and classification of hematological malignancies.

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Author and article information

Journal

Journal ID (nlm-ta): Blood

Journal ID (iso-abbrev): Blood

Journal ID (hwp): bloodjournal

Journal ID (pmc): blood

Journal ID (publisher-id): Blood

Title: Blood

Publisher: American Society of Hematology (Washington, DC )

ISSN (Print): 0006-4971

ISSN (Electronic): 1528-0020

Publication date (Print): 22 March 2018

Publication date (Electronic preprint): 12 January 2018

Publication date PMC-release: 22 March 2019

Volume: 131

Issue: 12

Pages: 1275-1291

Affiliations

[1 ]Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands;

[2 ]Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;

[3 ]Department of Clinical Immunology, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom;

[4 ]Hematology Biology, University Hospital Nantes, Nantes, France;

[5 ]Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy;

[6 ]Department of Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands;

[7 ]Division of Genetics & Molecular Medicine, King’s College, London, United Kingdom;

[8 ]MLL Munich Leukemia Laboratory, Munich, Germany;

[9 ]Centre for Trials Research, Cardiff University, Cardiff, United Kingdom;

[10 ]Myeloid Malignancies Section, National Institutes of Health, Bethesda, MD;

[11 ]Division of Pathology/Laboratory Medicine, Department of Hematopathology, MD Anderson Cancer Center, Houston, TX;

[12 ]Flow Cytometry Platform, University Hospital, Bordeaux, France;

[13 ]Center of Pathology, Laboratory of Hematology, University Hospital of Lille, Lille, France;

[14 ]Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands;

[15 ]Universitätsklinikum Carl Gustav Garus an der Technischen Universität Dresden, Dresden, Germany;

[16 ]Medical Research Council Molecular Haematology Unit, Oxford Centre for Haematology, University of Oxford and Oxford University Hospitals National Health Service Trust, Oxford, United Kingdom;

[17 ]Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;

[18 ]Department of Laboratory Medicine and

[19 ]Division of Hematology, Department of Medicine, University of Washington, Seattle, WA;

[20 ]Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany; and

[21 ]Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY